AKT1 E17K (allosteric inhibitor)

Class

selective, reversible allosteric inhibitor of the AKT1 E17K gain-of-function mutant, sparing wild-type AKT1/AKT2 to avoid the hyperglycemia and other toxicities seen with pan-AKT inhibitors; developed by Atavistik Bio

Pathway

blocks constitutive signaling driven by the AKT1 E17K mutation, which occurs as an acquired resistance mechanism to PI3Kα inhibitor treatment in ER+/HER2- breast cancer; studied as monotherapy and combined with fulvestrant in AKT1 E17K-mutant HR+/HER2- breast cancer

AKT1 is a serine/threonine kinase central to the PI3K/AKT/mTOR pathway, which relays growth-factor signals that promote cell survival, proliferation, and metabolism. In some breast cancers, a recurrent point mutation called E17K arises in AKT1's regulatory domain, locking the enzyme into a constitutively active state that no longer requires normal upstream activation. This mutation is notably associated with acquired resistance to PI3K-alpha inhibitors in hormone receptor-positive, HER2-negative breast cancer, where tumors reactivate downstream signaling despite upstream pathway blockade. An allosteric inhibitor selective for the E17K mutant form binds a site distinct from the kinase's catalytic pocket, exploiting the mutant's altered conformation to shut down its aberrant activity while sparing normal (wild-type) AKT1 and AKT2. This selectivity matters because wild-type AKT, particularly AKT2, plays an essential role in insulin signaling and glucose uptake in normal tissue; broadly inhibiting all AKT isoforms produces hyperglycemia and other metabolic toxicities. By targeting only the mutant enzyme, this approach aims to disrupt tumor-driving signaling with a narrower toxicity profile, and is being explored both alone and alongside endocrine therapy to counteract resistance that develops during treatment of hormone receptor-positive breast cancer.